Optimized pharmaceutical formulation for the treatment of inflammatory conditions of the esophagus

ABSTRACT

Disclosed is an optimized pharmaceutical formulation for the treatment of inflammatory conditions of the esophagus. A pharmaceutical formulation in the form of an orodispersible effervescent tablet is stable, easy to produce, and can be used without dissolving same in a liquid. It is not necessary to drink anything with the tablet as this would reduce the time that the budesonide solution remains in the affected regions of the esophagus. The effervescent tablet of the invention surprisingly resulted in an unexpectedly high rate of histological remission in patients with active eosinophilic esophagitis.

PRIORITY

This application is a continuation of U.S. application Ser. No.16/442,756 filed Jun. 17, 2019, which, in turn, is a continuation ofU.S. application Ser. No. 15/833,428 filed Dec. 6, 2017 (now U.S. Pat.No. 10,369,100 issued Aug. 6, 2019), which, in turn, is a continuationof U.S. application Ser. No. 15/107,735 filed Jun. 23, 2016 (now U.S.Pat. No. 9,867,780 issued Jan. 16, 2018), which, in turn, corresponds tothe U.S. national phase of International Application No.PCT/EP2014/078391, filed Dec. 18, 2014, which, in turn, claims priorityto European Patent Application No. 13.199278.6 filed Dec. 23, 2013, thecontents of which are incorporated by reference herein in theirentirety.

BACKGROUND OF THE INVENTION

For the treatment of inflammatory processes and conditions of theesophagus, such as for example the eosinophilic esophagitis, there isrequired a dosage form that upon oral use allows the local availabilityof the active ingredient budesonide at a sufficiently high concentrationat the focus of inflammation. This concept, referred to as esophagustargeting, cannot be realized with an oral application of a simpleactive ingredient solution, since there is a high risk in that then theactive ingredient is rapidly and almost quantitatively swallowed intothe stomach. Thus, the aim of the esophagus targeting preferably shouldbe achieved in that it is allowed for the active ingredient to slowlyslide along the mucosa of the esophagus associated with a completewetting of the surface as well as an adhesion of the active ingredient.This type of use selectively brings the active ingredient to the targetlocation. Furthermore, it is to be considered that the therapeutictreatment of the esophagus ideally makes additional specific demands onthe dosage form depending on which patient population is to be treated.The present invention is specifically suitable to provide anage-appropriate dosage form that can easily and reliably be used inadult patients and thus, achieves a high compliance of the prescribeddaily dose.

Eosinophilic esophagitis is a chronic, inflammatory disease of theesophagus that is accompanied with a hypofunction of the esophagus andis characterized in an infiltration of the esophageal epithelium witheosinophilic granulocytes. Eosinophilic esophagitis was casuisticallydescribed since the late 1970s and increasingly diagnosed since the late1990s. It seems to be present a Th2 cell-mediated response to airborneallergens and allergens taken in by food that results in the incretionof IL-13, IL-5 and subsequently in the increased production ofeotaxin-3. Hereby, eosinophilic granulocytes are attracted. Clinically,an often long-standing dysphagia as well as bolus impactions are ofimmediate importance. Making a diagnosis according to standard requiresthe detection of 15 eosinophils/high power field in the esophagus inpatients having symptoms of a dysfunction of the esophagus. In somepatients there are only observed mucosal changes that can easily beoverlooked. Eosinophilic esophagitis predominately affects men and oftenoccurs both in the childhood and the younger adulthood.

WO 2009/064417 discloses compositions for the treatment ofgastrointestinal inflammations. The compositions described therecomprise a corticosteroid and at least one additional agent for thetreatment of the inflammation. In WO 2009/064457 there are disclosedcorticosteroid-containing compositions that are suitable for thetreatment of inflammations of the gastrointestinal tract.

US 2007/0111978 describes methods of alleviating inflammatory diseasesof the gastrointestinal tract. It is suggested the preparation of ahighly viscous solution of a budesonide suspension with a very highconcentration of sucralose. US 2009/0264392 describes methods andcompositions that are suitable for the treatment of eosinophilicesophagitis. In this therapeutic method a steroid and an agent adheringto the mucosa are used.

It is an object of the present invention to provide pharmaceuticalformulations that on the one hand involve advantages in application andon the other hand can be easily prepared and provided in astorage-stable form.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical formulations, inparticular an effervescent tablet for orodispersible use that comprisesbudesonide or a pharmaceutically acceptable salt or derivative thereofas a pharmaceutical active ingredient and is preferably used in adultsfor the treatment of inflammatory diseases of the esophagus.

It is generally known to use effervescent tablets that after dissolutionin water are used as a drinking or rinse solution. Said use of theactive ingredient has various drawbacks for the described indicationsuch as for example the use of an increased volume of water (typically250 ml) and the associated dilution of the active ingredient ordistribution of the active ingredient throughout the oral cavity as wellas the commonly practiced fast swallowing of the solution into thestomach. Also known is the use of budesonide in eosinophilic esophagitis(Straumann et al., Gastroenterology, 2010. p. 1526-1537). However, inthis study liquid ampoules, so-called “Respules” were used, the normaluse of which is inhalation, wherein the content of the ampoule is filledinto an atomizer in advance and then, is inhaled. Deviating from thenormal use in the cited study the budesonide suspension of the ampoulewas used as a drinking solution.

However, the effervescent tablet according to the invention is notdiluted in water before use and thus, markedly differentiates from theusual manner of use of the effervescent tablets. The effervescent tabletaccording to the invention is not used to prepare a drinking solution,but is used orally and for example put on the tongue, preferably the tipof the tongue and slowly dissolves with salivary exposure in the mouth.Thus, the orodispersible effervescent tablet according to the inventiondiffers significantly from the known formulations in view of compositionand form.

The orodispersible effervescent tablet according to the invention canalso be referred to as lingual effervescent tablet, since duringapplication it should preferably be contacted with the tongue. Theformulation form can also be abbreviated as BUL (=budesonide-containinglingual effervescent tablet).

The orodispersible use of the effervescent tablet is a specific use formin which the tablet as such is orally used and for example, is put onthe tongue, preferably the tip of the tongue and after the mouth hasbeen closed is slightly pressed against the palate. In this way, theeffervescent reaction gets going and the salivation is stimulated withinca. 5-15 seconds. The constituents of the tablet start to dissolve inthe saliva. By the natural swallowing reflex then the saliva isswallowed in portions and continuously wets the esophagus, so that inthis way there is an adhesion of budesonide to the mucosa. During thedispersal of the effervescent tablet the patient swallows an average of5-10 times, so that the esophagus is permanently wetted with the activeingredient-containing saliva. The effervescent tablet disintegratescompletely and no noticeable fragments are left. Additional drinking ofliquid is not necessary, since no stimulus to drink is triggered. Thatis, an advantage of the optimized formulation is that no additionalliquid must be drunk, and thus, a sufficiently long retention time ofthe therapeutically active substance budesonide in the affected areas ofthe esophagus is ensured. The use is completed after 1.5 to 2 minutesand allows a concentrated distribution of budesonide on the esophagus.Here, the distribution of the active ingredient within the esophagus onthe mucosa of the esophagus exclusively is by saliva. Also, a widedistribution of budesonide already in the oral cavity is avoided. Theorodispersible effervescent tablet according to the invention can betaken by the patient very easy at appropriate times.

The orodispersible effervescent tablet according to the invention in useis put into the oral cavity of the patient where it rapidlydisintegrates into a plurality of small particles. Advantageously, theorodispersible effervescent tablet according to the invention not onlyhas the ability to rapidly disintegrate in case of a small amount ofliquid, i.e. preferably without additionally drinking a liquid. Anotheradvantage is an acceptable taste and a good mouth feel in use. Also ofadvantage is the sufficient fracture strength and high storage stabilityeven under conditions of a high temperature and high air humidity aswell as the possibility of a high loading with the active ingredientbudesonide. The orodispersible effervescent tablet according to theinvention has a high mechanical stability, which is why furtherprocessing, packaging, and transport are no problem. It is particularlynoteworthy that the orodispersible effervescent tablets according to theinvention have an improved long-term stability compared to the knownpharmaceutical formulations, what is demonstrated by tables 2 and 3, forexample.

The use of the effervescent tablet according to the inventionsignificantly reduces the risk of an undesired absorption of budesonideinto the systemic circle. So, there is no buccal or sublingual use ofthe dosage form. Moreover, in the normal use no relevant amounts ofbudesonide are absorbed through the oral mucosa. In contrast to orallydisintegrated tablets, that also are orodispersibly used, there is theclear advantage that the dispersal of the effervescent tablets allows acontinuous release lasting 1.5 to 2 minutes and thus, a topicapplication of the active ingredient to the mucosa of the esophagus.However, orally disintegrated tablets for use have the drawback thatthey immediately disintegrate and therefore, can only be taken in onegulp. Moreover, compared to orally disintegrated tablets effervescenttablets are manufactured industrially much simpler.

Thus, the object of the present invention are orodispersibleeffervescent tablets containing 0.25 mg to 5 mg of budesonide,preferably 0.3 to 4 mg, more preferably 0.4 to 3 mg, and most preferably0.5 to 2.0 mg of budesonide. The budesonide used can be used in anypharmaceutically applicable form. The given amount represents the totalamount of the active ingredient budesonide in an orodispersibleeffervescent tablet. In a preferred embodiment the orodispersibleeffervescent tablet according to the invention does not contain anyfurther pharmaceutical active ingredient.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 presents a bar graph depicting the mean load with eosinophils,measured as a mean number of eosinophils/mm² hpf, in the proximal, thecentral (Mid) and the distal esophageal segments subsequent to treatmentwith an orodispersible, budesonide-containing effervescent tablet of thepresent invention (BUET), either as a twice-daily dose of one tabletwith 1 mg of active ingredient (BUET 2×1 mg) or as a twice-daily dose ofone tablet with 2 mg of active ingredient (BUET 2×2 mg), as compared toa Placebo.

FIG. 2 presents a bar graph depicting the mean total endoscopicintensity score subsequent to the two treatments (BUET 2×1 mg and BUET2×2 mg) as compared to a Placebo.

FIG. 3 graphically depicts the long-lasting clinical effect subsequentto the two treatments (BUET 2×1 mg and BUET 2×2 mg) as compared to aPlacebo.

FIG. 4 graphically demonstrate the frequency of dysphagia eventssubsequent to the two treatments (BUET 2×1 mg and BUET 2×2 mg) ascompared to a Placebo.

DETAILED DESCRIPTION OF THE INVENTION

An essential component of the orodispersible effervescent tablet is asystem that can generate a gas in the presence of saliva so as toachieve the effervescent effect. It is required that said gas generatingsystem is pharmaceutically acceptable. On the one hand, such a gasgenerating system is comprised of a weak acid or a salt of a weak acid,respectively. In the presence of water the free weak acid arises fromthis. However, the acid must not be too strong in order to avoid healthproblems. This may be tartaric acid, acetic acid, lactic acid, and morepreferably citric acid. Usually, the salts of the acids are used, i.e.for example sodium, magnesium, or calcium salts. The other component ofthe gas generating system is comprised of a salt of an acid that inconjunction with a further acid can release a gas. Preferably, these aresalts of the carbonic acid. These may be carbonates or hydrogencarbonates, such as for example sodium or potassium carbonate or sodiumor potassium hydrogen carbonates or calcium carbonates as well asmixtures of these salts. It is essential that a gas perfectly safe forhealth, namely CO₂, is released in small amount during use of theeffervescent tablet. The gas is released by the interaction of the gasgenerating components with the saliva.

An orodispersible effervescent tablet according to the invention has amass that is between 100 mg and 200 mg, preferably the orodispersibleeffervescent tablets have a mass of 120 mg to 160 mg. Most preferredembodiments of the orodispersible effervescent tablets have a mass of133 mg to 147 mg.

Also the size of the effervescent tablet according to the invention isessential. Preferably, the effervescent tablets have a diameter between5 and 10 mm. Preferably, the effervescent tablets are round, although avery round shape being not necessarily required. Deviations from theround shape may also be selected. Preferably, the effervescent tabletsare biplane with the diameter preferably being between 6.0 and 8.0 mm,and more preferably between 6.9 and 7.3 mm. The height of theorodispersible effervescent tablet is preferably between 1.5 and 3.0 mm,more preferably between 1.6 and 2.8 mm, and most preferably between 1.8and 2.6 mm.

As to the mechanical properties of the orodispersible effervescenttablet these are essential. The fracture strength of the effervescenttablet is preferably between a value of 10 and 100 N, more preferablybetween 20 N and 70 N, and is preferably determined according to theEuropean Pharmacopoeia in accordance with the 2.9.8. monography.

During the test of the mechanical strength of tablets the solid specimenis clamped between two plungers or a plunger and an anvil. Then, a forceis applied to the specimen (tablet) and the force required to cause abreak in the tablet is determined. Determination of the fracturestrength of the orodispersible effervescent tablet according to theinvention can be performed for example with fully automatic testdevices. For example, such test systems are offered by Pharmatest underthe designation WHT 3ME. Of course, equivalent test apparatus can alsobe used.

The preferable fracture strength on the one hand allows a good andreproducible industrial manufacture, but also a sufficient mechanicalstability. According to the invention, the orodispersible effervescenttablets have a friability (abrasion strength) of at most 5%, preferablyat most 1%. The friability (abrasion strength) is preferably determinedin accordance with the European Pharmacopoeia according to the 2.9.7.monography.

Shape, consistency, and mechanical properties of the orodispersibleeffervescent tablet are essential, since on the one hand the size andshape allow the continuous and relatively uniform dispersal in thepresence of saliva. On the other hand, they allow a sufficientmechanical stability, so that the effervescent tablet in the normal usedoes not prematurely break into pieces and because of that a useaccording to the invention is no longer possible. The properties of theorodispersible effervescent tablet have the effect that no foreign-bodysensation develops in the mouth and thus, the use is found to besubjectively pleasant by the patient.

The properties of the effervescent tablet described in the particularlypreferred embodiment allow the variable single dose administration ofbudesonide in an amount of preferably 0.5 to 3 mg of budesonide. Here,the amount of active ingredient processed has no effect on the describedquality parameters that are relevant for the use, such as size, shape,and mechanical stability. Dividing the tablet is not necessary, ratherone tablet corresponds to the dose to be used.

The less the dose of budesonide in the effervescent tablet, the higherthe demands on the selection of suitable excipients for ensuring asufficient long-term stability of the dosage form. Then, an undesireddecomposition of the active ingredient would be particularly undesiredif low doses are administered, because then the pharmaceuticallysufficient amount of the active ingredient would no longer be present inthe tablets. Surprisingly, it was shown that the physicochemicalstability of budesonide in the effervescent tablet is only allowed bythe composition according to the invention. Even if individualexcipients are part of the prior art of effervescent tablets, preferablyonly exactly with the qualitative and quantitative composition accordingto the invention a long-term stability of the dosage form of up to 36months for all dosage strengths of a budesonide effervescent tablet fororodispersible use is possible. The effervescent tablets according tothe invention can be stored at room temperature.

In a preferred embodiment, an orodispersible effervescent tabletaccording to the invention contains a polyvinylpyrrolidone. These arepolymerization products of the vinylpyrrolidone. The low molecularpolyvinylpyrrolidones are hygroscopic, according to the invention it isparticularly preferred to use the povidone K25. It is also possible touse derivatives of polyvinylpyrrolidone that are known in this field.The amount of polyvinylpyrrolidone used (for example povidone K25) ispreferably 1 to 10, more preferably 1.5 to 3.5% by weight, based on thefinished tablet.

It is required for the orodispersible effervescent tablet according tothe invention to have a pleasant taste. Thus, in a preferred embodimentthere is added a substance that leaves a sweet taste upon dissolution inthe mouth. Since the use of sucrose can be detrimental, preferably analternative sweetener is used. In a preferred embodiment this issucralose. Sucralose is sucrose with the hydroxyl residues beingreplaced by chlorine atoms. Compared to sucrose sucralose issignificantly sweeter. However, the manufacturing conditions and otherconstituents of the orodispersible effervescent tablet have to beadjusted such that no dispersal of the sucralose occurs that could leadto undesired discolorations. In the orodispersible effervescent tabletthe proportion of sucralose preferably is between 0.1 and 1.0% byweight, more preferably between 0.2 and 0.6% by weight, based on thefinished tablet.

A further preferably used constituent of the orodispersible effervescenttablet is docusate sodium. This is a white, wax-like substance that isused as a solubilization and emulsifying agent in particular to theactive ingredient budesonide. The amount of docusate sodium preferablyis between 0.01 and 0.2% by weight, more preferably 0.02 to 0.15% byweight, based on the finished tablet.

A further preferably used excipient is mannitol. The mannitol used inaccordance with the invention in preferred embodiment is a polymorph,crystalline solid. The two most often characterized modifications are βand α mannitol that are also designated as modifications I and II. Asfurther modification there was also described δ mannitol. For themanufacture of the orodispersible effervescent tablets according to theinvention the properties of the excipients, particularly that of themannitol, have to meet special requirements. On the one hand it isrequired that the powder mixtures during the manufacture have a goodflowability, on the other hand an optimum compactness is essential, i.e.the ability to form tablets of high strength with low compacting force.Here, the particle size distribution of the individual mannitol crystalscan play a central role. According to the invention there is preferablyused an amount of 2.0 to 10.0% by weight, more preferably 4.0 to 7.0% byweight of mannitol, based on the finished tablet.

A further important excipient that is preferably used in accordance withthe invention are polyethylene glycols. In a preferred embodimentmacrogol 6000 is used in an amount of 1.0 to 10% by weight, preferably2.0 to 7.0% by weight, based on the finished tablet.

A further preferred excipient component is magnesium stearate that ispreferably used in an amount of 0.01 to 0.5% by weight, more preferablyin an amount of 0.05 to 0.15% by weight.

The components that achieve the effervescent effect in terms of theweight make up the main part of the orodispersible effervescent tablet.Here, in a preferred embodiment this is a mixture of disodium citrate,monosodium citrate as well as sodium hydrogen carbonate. Saideffervescent mixture makes up a proportion of weight of about 70 to 95%by weight, preferably 85 to 92% by weight, based on the finishedorodispersible effervescent tablet. It is especially the particle shapeof the components of the effervescent mixture that is relevant for themechanical properties of the orodispersible effervescent tablet. Thus,from the available qualities of the individual components there must beselected those which in cooperation with the other excipients and thepharmaceutically active ingredient budesonide can be compacted such thatthe properties of the finished orodispersible effervescent tablet,particularly the intended fracture strength and friability, can beachieved.

Of course, all of the components of the orodispersible effervescenttablet must add up to 100% by weight.

The orodispersible effervescent tablet according to the inventionpreferably can be used for the treatment but also for the prevention ofinflammatory conditions of the esophagus. The formulation according tothe invention allows a continuous delivery of the active ingredient thatis pleasant for the patient and that is relatively uniformly distributedon the esophagus. Thus, the active ingredient budesonide is targetedlyand efficiently topically brought to the inflammatory regions of theesophagus. The orodispersible effervescent tablets according to theinvention are particularly preferably used for the treatment ofeosinophilic esophagitis.

Preferred embodiments of the present invention are explained by thefollowing examples.

Example 1

It was surprisingly found that a physicochemical stability of thebudesonide effervescent tablets of up to 36 months as well as thequality parameters relevant for the use of the effervescent tablet suchas size, shape, and mechanical stability can be achieved by thequalitative and quantitative composition given in table 1.

In table 1, there are given particularly preferred concentrationinformation of the components that are preferably used according to theinvention. It has not necessarily fully been complied with the valuesgiven in the table. However, the essential components and the ratios ofthe individual components to each other are decisive for theadvantageous properties of the orodispersible budesonide effervescenttablets according to the invention.

TABLE 1 Composition of preferred budesonide effervescent tabletsComposition [mg] Budesonide Budesonide Budesonide 0.5 mg 1 mg 2 mgEffervescent Effervescent Effervescent tablet tablet tablet GranulateBudesonide 0.50 1.00 2.00 Disodium citrate 67.00 67.00 67.00 Monosodiumcitrate 15.00 15.00 15.00 Sodium hydrogen 45.00 45.00 45.00 carbonatePovidone K25 2.00 2.00 2.00 Sucralose 0.30 0.30 0.30 Docusate sodium0.05 0.05 0.05 Sum 129.85 130.35 131.35 Final mixture Mannitol 5.95 5.955.95 Macrogol 6000 5.00 5.00 5.00 Magnesium stearate 0.10 0.10 0.10 Sum140.90 141.40 142.40

Example 2

The results of the durability tests of budesonide 1 mg effervescenttablets at different storage conditions are summarized in table 2.Compared to the initial values even during the storage under theconditions of loading tests no relevant changes were shown.

TABLE 2 Stability results of budesonide 1 mg effervescent tabletsStorage period at 25° C./60% relative humidity in months Initially 3 6 912 18 24 Fracture strength 36 33 35 35 36 36 35 [N] Dispersal in water1.3 1.4 1.3 1.8 1.5 1.4 2.9 [Minutes] Content of budesonide 101.4 99.5100.0 100.7 99.5 99.9 98.0 [%] Sum of total impurities <0.1 0.13 0.110.12 0.13 0.19 0.22 [%] Storage period at 30° C./65% relative humidityin months Initially 3 6 9 12 18 Fracture strength 36 37 34 36 34 28 [N]Dispersal in water 1.3 1.7 1.5 1.7 1.7 2.9 [Minutes] Content ofbudesonide 101.4 100.5 99.6 100.0 98.1 97.3 [%] Sum of total impurities<0.1 0.13 0.12 0.15 0.18 0.40 [%] Storage period at 40° C./75% relativehumidity in months Initially 1 2 3 Fracture strength 36 21 36 38 [N]Dispersal in water 1.3 0.9 1.7 1.8 [Minutes] Content of budesonide 101.4100.2 100.6 99.5 [%] Sum of total impurities <0.1 0.14 0.27 0.39 [%]

Example 3

Compared to the initial values especially during the storage under thecondition of climatic zone II no relevant changes are shown. Incontrast, the results of table 3 demonstrated that in case of only aslight deviation from this recipe (e.g. exchange of 0.40 mg sucralosewith 1.0 mg aspartame) the long-term stability of the budesonide 1 mgeffervescent tablets is no longer given. As the failed attempt revealsimpressively, in case of a changed recipe the decomposition ofbudesonide after equally long storage periods increases by a factor ofca. 7. Since this decomposition turns out even more clearly with dosagesof less than 1 mg of budesonide the physicochemical stability of theeffervescent tablet is preferably given with the qualitative andquantitative composition given in table 1. With less than 1 mg ofbudesonide per orodispersible effervescent tablet the instability turnsout even more clearly.

TABLE 3 Lacking stability of budesonide 1 mg effervescent tablets withmodified composition Storage period at 25° C./60% relative humidity inmonths Initially 3 6 9 12 18 27 Content of 98.6 99.7 101.1 99.8 98.996.8 95.7 Budesonide [%] Sum of total <0.1  0.31  0.66  0.86  0.81  1.05 1.63 impurities [%] Storage period at 30° C./65% relative humidity inmonths Initially 3 6 9 12 Content of 98.6 100.1 100.4 99.4 98.2Budesonide [%] Sum of total <0.1  <0.1  0.91  1.01  1.31 impurities [%]

In this test, 0.4 mg of sucralose were replaced by 1.0 mg aspartame.

Example 4

Clinical Data:

In a 4-arm, double blind, randomized, placebo-controlled phase IImulticenter study 2×1 mg/day or 2×2 mg/day of budesonide effervescenttablets were compared with 2×2 mg/day oral viscous budesonide suspensionor placebo in the treatment of active eosinophilic esophagitis. Blindingwas ensured by using the “Double-Dummy” technique. The aim of the studywas to show the superiority of the budesonide formulations over placebo.The first primary partial endpoint of said study was the rate of thehistological remission, wherein the eosinophils (eos) of the patients inremission had to attain mean number of <16 eos/mm² hpf (“high powerfield”, i.e. the visual field in the microscope at a magnitude of 400×)after 2 weeks of treatment. As the second primary partial endpoint thedifference in the mean number of eos/mm² hpf between the beginning ofthe study and the end of the treatment was measured. Both describedefficacy parameters were confirmatively examined in a closed test methodto enable a comparison of all three verum groups with the placebo group.The design of the study including the described endpoints is virtuallyidentical to the study described in the publication of Straumann, 2010loc. cit.

Surprisingly, the results of all three test formulations not only weresignificantly better than that of the placebo, but also better than thatof the budesonide formulation that is described in the work of Straumannet al., 2010 loc. cit., in the dosage of 2×1 mg/day this result issignificant.

Table 4 shows the results for the histological remission defined as anaverage of <16 eos/mm² hpf. Patients that prematurely left the studywithout a histological secondary inspection having taken place wereanalyzed as patients that are not in remission. In a sensitivityanalysis only patients were analyzed who had completed the study.

TABLE 4 Histological Remission Number (%) of patients with histologicalremission BUU-2/EEA Straumann (2010 loc. cit.) Budesonide BudesonideBudesonide 2 × 1 mg 2 × 2 mg 2 × 1 mg Tablet Tablet Placebo suspensionPlacebo FAS at wk 12** (LOCF) ITT 19/19 (100%) 18/19 (95%) 0/19 (0%)13/18 (72%) 2/18 (11%) [95% RCI] [64.7%; 100%] [57.6%; 99.5%] — NA —p-value * <0.0001 <0.0001 — <0.0001 — PP at wk 12** (LOCF) ITT 19/19(100%) 17/17 (100%) 0/17 (0%) — — [95% RCI] [63.1%; 100%] [61.3%; 100%]— — — p-value * <0.0001 <0.0001 — — — histological Remission defined as<5 eos/hpf (corresponding to <16 eos/mm² hpf) FAS, Full Analysis Set;PP, Per Protocol Analysis Set; RCI, repeated confidence interval (forthe difference between verum and placebo) * for the superiority of verumover placebo **at wk 12. at 12 weeks

Also for the analysis of the co-primary endpoint the superiority overthe placebo could be shown (table 5). (The comparison with Straumann isnot possible, since this endpoint was not studied in Straumann).

TABLE 5 Difference in the mean number eos/mm² hpf (FAS) BudesonideBudesonide Budesonide 1 mg Tablet 2 mg Tablet 2 mg Susp. Placebo (n =19) (n = 19) (n = 19) (n = 19) mean −119.919 (79.275) −128.120 (78.457)−96.665 (124.253) −7.882 (157.939) (SD) n n = 19 n = 18 n = 18 n = 19p-value * 0.0006 0.0005 0.0041 — * for the superiority of verum overplacebo

Additionally, it could be shown for all verum groups that in allesophagus segments the load with eosinophils was almost completelyeliminated (in a region of 0.2-2.7 eos/mm² hpf). This result confirmsthat the pharmaceutical formulation according to the inventionesophagus-selectively distributes the active ingredient over the entireesophagus. This is illustrated in FIG. 1.

FIG. 1 shows the mean load with eosinophils in the respective esophagussegment. The esophagus was divided in proximal part, central part (Mid)and the distal part. It was given the mean number of eosinophils/mm²hpf. The abbreviation EOT means “End of Treatment”.

Example 5

In addition to the described efficacy on the histology it was shown thata 2-week treatment with the formulation according to the invention alsoresults in a statistically significant and clinically relevantimprovement of the eosinophilic esophagitis, based on the endoscopicimage. This is illustrated in FIG. 2.

In FIG. 2 there is given the mean total endoscopic intensity score. Theabbreviation BUET means orodispersible, budesonide-containingeffervescent tablet. The abbreviation 2×1 mg means twice-daily dose ofone tablet with 1 mg of active ingredient. The abbreviation 2×2 mg meanstwice-daily dose of an orodispersible effervescent tablet with 2 mg ofactive ingredient.

Baseline means the baseline, EOT means “End of Treatment”. Here,Baseline means the first visit of the patient on which the treatmentstarts and EOT is the last visit during the treatment. Since there isalways applied the principle of the LOCF (last observation carriedforward) the EOT visit can take place at different times, but alwayswith all test parameters according to the protocol of the last visit ofthe patients.

Example 6

The orodispersible effervescent tablets according to the invention with2 mg of budesonide per tablet in a study were administered to a group ofpatients between 20 and 50 years of age. The patients were treated in atest group with one 2 mg budesonide tablet per day. The control groupgot an orodispersible effervescent tablet without active ingredient(placebo). During a 15-days treatment it was found that theorodispersible budesonide-containing effervescent tablet was welltolerated and that the histological and clinical parameters weresignificantly improved in contrast to the placebo group. Theorodispersible effervescent tablet in view of the applicability by alltest persons was entirely evaluated as positive.

Example 7

In further examinations, serum/biomarkers for monitoring and checkingthe response to therapy of a medication of the eosinophilic esophagitis(EoE) were identified. In the clinical study there were included EoEpatients who have received a topical steroid therapy (the orodispersibleeffervescent tablet according to the patent). Various serum markers weretested for their suitability to what extent the response to therapy andthe success of the therapy correlate with the changes of these serummarkers. The sample material for the serum samples is derived from theclinical study described in the patent application (Example 4).

The “eosinophilic cationic protein, ECP” proved to be particularlysuitable as a marker. This is a cytotoxic protein that is released fromthe granules of activated eosinophilic granulocytes (Rothenberg,Gastroenterology 2009, 1238-1249). It is known that this protein seemsto be suitable for monitoring the response of therapy under topicalfluticasone (Schlag et al., J Clin Gastroenterol. 2014, 600-606).

It was surprisingly found that ECP not only reflects the clinicalresults. In addition to the clear correlation between the histologicalremission and the decrease in the serum level of ECP during the 2-weekstreatment with 1 and 2 mg, respectively, of orodispersible budesonideeffervescent tablets there was also shown a lasting therapy successafter completion of the 2-weeks treatment. This is illustrated in FIG. 3(right illustration on “Follow-up Phase, FU”; duration of FU: 2 weeks).

From the experiments performed an additional effect can be deduced. Theformulation according to the invention in addition to the effectivetreatment is also suitable to achieve an ongoing post-treatment clinicaleffect. It does not come to the frequently observed “rebound effect”when a drug therapy is completed.

Example 8

Specification of the Long-Lasting Clinical Effect

The long-lasting clinical effect can be shown from additionallyperformed tests by illustrating the dysphagia score in thetreatment-free follow-up period. Said instrument, the so-called “patientreported outcome”, demonstrates the frequency of dysphagia events from 0(no event) to 4 (several events per day) as well as the intensity ofthese events from 0 (no difficulties in swallowing) to 5 (long-lasting,complete obstruction that requires an endoscopic intervention). Theresults of the BUU-2 study for this score show that the treatmenteffect, measured as mean change (in %), lasts between the last treatmentand the end of the follow-up period in the verum groups (1 mg and 2 mgof budesonide). In both groups this change is negative, i.e. the scorehas improved from a higher to a lower value. In the placebo group saidvalue with +25.5% has deteriorated significantly. The results of thesetests are summarized in FIG. 4.

What is claimed:
 1. An orodispersible effervescent tablet formulated torelease budesonide in an oral cavity for a period of 1.5 minutes to 2minutes, said tablet comprising: a. 0.25 mg to 5 mg of budesonide, andb. a gas generating system comprising (i) a weak acid or salt thereof,and (ii) a salt of an acid that, in conjunction with a further acid, canrelease a gas and produce an effervescent reaction upon contact withsaliva, wherein said effervescent reaction provides a concentrateddistribution of budesonide targeted directly to one or more inflammatoryregions of an esophageal mucosa while minimizing undesired absorption ofbudesonide into systemic circulation and/or through an oral mucosa. 2.The tablet of claim 1, wherein the amount of budesonide present in saidtablet ranges from 0.25 mg to 5 mg.
 3. The tablet of claim 1, whereinsaid tablet further comprises 0.1% to 1.0% by weight sucralose, based onthe weight of the finished tablet.
 4. The tablet of claim 1, whereinsaid tablet further comprises 0.01% to 0.2% by weight docusate sodium,based on the weight of the finished tablet.
 5. The tablet of claim 1,wherein said tablet further comprises polyvinylpyrrolidone.
 6. Thetablet of claim 1, wherein said tablet further comprises mannitol. 7.The tablet of claim 1, wherein said tablet further comprises macrogol6000.
 8. The tablet of claim 1, wherein said tablet further comprisesmagnesium stearate.
 9. The tablet of claim 1, wherein said tablet has adiameter of 5 to 10 mm.
 10. The tablet of claim 1, wherein said tablethas a height of 1.5 to 3.0 mm.
 11. The tablet of claim 1, wherein saidtablet has a mass of 100 mg to 200 mg.
 12. The tablet of claim 1,wherein said tablet has a fracture strength of 10 N to 100 N.
 13. Thetablet of claim 1, wherein said tablet has a friability of at most 5%.14. The tablet of claim 1, wherein (b)(i) comprises a pharmaceuticallyacceptable weak acid or salt thereof that decreases the pH value in anaqueous solution, and (b)(ii) comprises a salt of a pharmacologicallyacceptable acid.
 15. The tablet of claim 14, wherein (b)(i) is selectedfrom the group consisting of tartaric acid, acetic acid, lactic acid,and citric acid.
 16. The tablet of claim 14, wherein (b)(i) is selectedfrom the group consisting of sodium, magnesium, and calcium salts oftartaric acid, acetic acid, lactic acid, or citric acid.
 17. The tabletof claim 14, wherein (b)(i) is selected from the group consisting ofdisodium citrate, monosodium citrate, and mixtures thereof.
 18. Thetablet of claim 14, wherein (b)(ii) is a salt of carbonic acid.
 19. Thetablet of claim 14, wherein (b)(ii) is selected from the groupconsisting of carbonates and hydrogen carbonates.
 20. The tablet ofclaim 14, wherein (b)(ii) is selected from the group consisting ofNaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, CaCO₃, and mixtures thereof.
 21. Anorodisperisble effervescent tablet formulated to deliver budesonidedirectly to an esophageal mucosa in a subject in need thereof, saidtablet comprising: a. 0.1 to 20 mg budesonide; and b. a gas generatingsystem comprising (i) a weak acid or salt thereof, and (ii) a salt of anacid that, in conjunction with a further acid, can release a gas;wherein said gas generating system generates an effervescent reactionupon contact with saliva that causes said tablet to disintegrate into aplurality of small budesonide-containing particles that, in turn,suspend in saliva, further wherein said particle-containing saliva, whenswallowed, is relatively uniformly distributed on the subject'sesophagus to form a budesonide-containing adhesion that provides aconcentrated distribution of budesonide targeted directly toinflammatory regions of the subject's esophageal mucosa while minimizingabsorption through the subject's oral mucosa.
 22. The tablet of claim21, wherein localized budesonide delivery extends for 1.5 to 2 minutes.